EP2471788B1 - Amycolose derivative, and production process and use of same - Google Patents

Amycolose derivative, and production process and use of same Download PDF

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EP2471788B1
EP2471788B1 EP10811761.5A EP10811761A EP2471788B1 EP 2471788 B1 EP2471788 B1 EP 2471788B1 EP 10811761 A EP10811761 A EP 10811761A EP 2471788 B1 EP2471788 B1 EP 2471788B1
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Prior art keywords
compound
salt
amycolamicin
particularly limited
appropriately selected
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French (fr)
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EP2471788A1 (en
EP2471788A4 (en
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Shigehiro Tohyama
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Microbial Chemistry Research Foundation
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Microbial Chemistry Research Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/10—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C12P19/46—Preparation of O-glycosides, e.g. glucosides having an oxygen atom of the saccharide radical bound to a cyclohexyl radical, e.g. kasugamycin

Definitions

  • the present invention relates to new compound amycolose derivatives, and a method for producing the same, and use of the same.
  • WO 2005/100342 discloses pyrrole derivatives suitable for the treatment of cancer.
  • an object of the present invention is to provides a new compound easy to produce and having an excellent cell growth suppressive activity or a salt thereof; a method for producing the new compound or the salt thereof; and a pharmaceutical composition containing the new compound or the salt thereof.
  • the compound having a structure expressed by the above Structural Formula (4) is a compound that was previously isolated by the present applicants and named "amycolamicin.”
  • the amycolamicin is produced from Amycolatopsis sp. MK575-fF5 strain (FERM P-21465) and has an excellent antibacterial activity.
  • the present invention is based on the above findings obtained by the present inventor. Means for solving the problems are as follows.
  • the present invention can provide: a new compound easy to produce and having an excellent cell growth suppressive activity or a salt thereof; a method for producing the new compound or the salt thereof; and a pharmaceutical composition containing the new compound or the salt thereof.
  • a compound of the present invention is represented by the following General Formula (1).
  • the compound represented by the General Formula (1) is a new compound obtained by the present inventor and may be referred to as an "amycolose derivative": where "R” denotes a hydrogen atom or an alkyl group.
  • amycolose derivative represented by the General Formula (1) where "R” is a hydrogen atom is a compound having a structure expressed by the following Structural Formula (1):
  • compound 1 The following are physico-chemical properties of the compound having a structure expressed by the Structural Formula (1) (hereinafter may be referred to as "compound 1").
  • the analysis method usable for confirming that the compound 1 has a structure expressed by the Structural Formula (1) is not particularly limited and may be appropriately selected from various analysis methods depending on the intended purpose.
  • Examples of the analysis method include a method of measuring, for example, mass spectrum, 1 H nuclear magnetic resonance spectrum, 13 C nuclear magnetic resonance spectrum or infrared absorption spectrum.
  • the compound 1 may be in the form of a salt.
  • the salt is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include: addition salts formed with inorganic acids such as hydrochloric acid and sulfuric acid; addition salts formed with organic acids such as formic acid, acetic acid, trifluoroacetic acid and tartaric acid; salts formed with alkali metals such as sodium and potassium; salts formed with alkaline earth metals such as calcium and magnesium; and salts formed with organic amines such as methylamine, ethylamine and diethanolamine.
  • the compound 1 has tautomerism and thus encompasses tautomers thereof.
  • the compound 1 or the salt thereof may be derived from the compound having a structure represented by the following Structural Formula (4) (hereinafter may be referred to as "amycolamicin”) or may be obtained through chemical synthesis. Among them, the compound 1 or the salt thereof is preferably obtained by the below-described method of the present invention for producing the compound or the salt thereof.
  • the compound having a structure represented by the General Formula (1) where "R” is an alkyl group is not particularly limited, so long as “R” is an alkyl group, and may be appropriately selected depending on the intended purpose. It is preferably a compound where "R” is a methyl group, more preferably a compound having a structure expressed by at least one of the following Structural Formulas (2) and (3):
  • compound 2 The following are physico-chemical properties of the compound having a structure expressed by the Structural Formula (2) (hereinafter may be referred to as "compound 2").
  • the analysis method usable for confirming that the compound 2 has a structure expressed by the Structural Formula (2) is not particularly limited and may be appropriately selected from various analysis methods depending on the intended purpose.
  • Examples of the analysis method include a method of measuring, for example, mass spectrum, 1 H nuclear magnetic resonance spectrum, 13 C nuclear magnetic resonance spectrum or infrared absorption spectrum.
  • the compound 2 may be in the form of a salt.
  • the salt is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include: addition salts formed with inorganic acids such as hydrochloric acid and sulfuric acid; addition salts formed with organic acids such as formic acid, acetic acid, trifluoroacetic acid and tartaric acid; salts formed with alkali metals such as sodium and potassium; salts formed with alkaline earth metals such as calcium and magnesium; and salts formed with organic amines such as methylamine, ethylamine and diethanolamine.
  • the compound 2 or the salt thereof may be derived from amycolamicin or may be obtained through chemical synthesis. Among them, the compound 2 or the salt thereof is preferably obtained by the below-described method of the present invention for producing the compound or the salt thereof.
  • compound 3 The following are physico-chemical properties of the compound having a structure expressed by the Structural Formula (3) (hereinafter may be referred to as "compound 3").
  • the analysis method usable for confirming that the compound 3 has a structure expressed by the Structural Formula (3) is not particularly limited and may be appropriately selected from various analysis methods depending on the intended purpose.
  • Examples of the analysis method include a method of measuring, for example, mass spectrum, 1 H nuclear magnetic resonance spectrum, 13 C nuclear magnetic resonance spectrum or infrared absorption spectrum.
  • the compound 3 may be in the form of a salt.
  • the salt is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include: addition salts formed with inorganic acids such as hydrochloric acid and sulfuric acid; addition salts formed with organic acids such as formic acid, acetic acid, trifluoroacetic acid and tartaric acid; salts formed with alkali metals such as sodium and potassium; salts formed with alkaline earth metals such as calcium and magnesium; and salts formed with organic amines such as methylamine, ethylamine and diethanolamine.
  • the compound 3 or the salt thereof may be derived from amycolamicin or may be obtained through chemical synthesis. Among them, the compound 3 or the salt thereof is preferably obtained by the below-described method of the present invention for producing the compound or the salt thereof.
  • the above amycolose derivatives or salts thereof have an excellent cell growth suppressive activity.
  • the amycolose derivatives or the salts thereof can suitably be used as an active ingredient of the below-described pharmaceutical composition of the present invention.
  • a method for producing the compound of the present invention i.e., amycolose derivatives, or the salt thereof includes: culturing a microorganism belonging to the genus Amycolatopsis and capable of producing amycolamicin or a salt thereof isolating the amycolamicin or the salt thereof from a culture obtained from the culturing; and decomposing the amycolamicin or the salt thereof.
  • physiologically active compounds produced by microorganisms have complex structures and thus are difficult to produce through synthetic organic chemistry.
  • derivatives having their partial structures essential for development of physiological activities can easily be obtained, and used for the synthesis of compounds having a higher cell growth suppressive activity, which is advantageous.
  • amycolamicin is produced as follows. Specifically, microorganisms that produce the amycolamicin (hereinafter may be referred to as "amycolamicin-producing microorganisms") are inoculated into a nutrient medium and cultured at a temperature suitable for the production of the amycolamicin, whereby a culture containing the amycolamicin is obtained.
  • the nutrient medium used for the above culturing is nutrient media that can be used for culturing actinomycetes.
  • the nutrient sources which can be added to the nutrient medium include nitrogen sources such as commercially available soy flour, peptone, yeast extract, meat extract, corn steep liquor and ammonium sulfate; carbon sources such as fats and carbohydrates; e.g., tomato paste, glycerin, starch, glucose, galactose and dextrin.
  • inorganic salts such as sodium chloride and calcium carbonate may be added to the medium before use. If necessary, a trace amount of a metal salt may be added to the medium before use. Any known material for culturing actinomycetes may be used so long as the material can be utilized by the amycolamicin-producing microorganisms to promote the production of the amycolamicin.
  • the production of the amycolamicin uses the microorganism belonging to the genus Amycolatopsis and capable of producing the amycolamicin.
  • a microorganism of Amycolatopsis sp. MK575-fF5 strain (FERM P-21465) can produce the amycolamicin.
  • other strains that are capable of producing the amycolamicin can be isolated from the natural world by a routine method for insolating amycolamicin-producing microorganisms.
  • mutation treatments such as exposure to radiation
  • the microorganism of Amycolatopsis sp. MK575-fF5 strain and other microorganisms capable of producing the amycolamicin can be mutated so that they have increased production capability of the amycolamicin.
  • the amycolamicin can be produced through genetically engineering techniques.
  • the seed culture used for the production of the amycolamicin may be, for example, the growth culture obtained through slant culturing of the amycolamicin-producing bacteria on an agar medium.
  • the amycolamicin-producing bacteria be aerobically cultured in an appropriate medium.
  • a routine method can be used for isolating the target compound from the resultant culture.
  • the culturing temperature is not particularly limited and may be determined depending on the type of the amycolamicin-producing microorganisms, so long as the growth of the amycolamicin-producing microorganisms is not substantially inhibited and the amycolamicin-producing microorganisms can produce the amycolamicin.
  • the culturing temperature is preferably 25°C to 35°C.
  • the production of the amycolamicin by the Amycolatopsis sp. MK575-fF5 strain generally becomes maximum for 3 days to 9 days.
  • a change over time in the titer of the amycolamicin in the culture can be measured through, for example, HPLC or a cylinder plate method using Staphylococcus aureus or other bacteria as tested bacteria.
  • the amycolamicin is isolated from the obtained culture.
  • the isolation method may appropriately utilize a method used for isolating metabolites produced by microorganisms.
  • Examples of the isolation method for the amycolamicin include a method by extracting with a water-immiscible solvent, a method utilizing differences in adsorption affinity to various adsorbents, gel filtration, chromatography utilizing countercurrent distribution, and combinations thereof.
  • the separated microorganisms are treated with an extracting method using an appropriate organic solvent or an eluting method through disruption of microorganisms, whereby the amycolamicin can be isolated through extraction of the microorganisms and isolation/purification as described above.
  • the production method can be performed as described above to produce the amycolamicin.
  • the amycolamicin has tautomerism and thus encompasses tautomers thereof.
  • amycolamicin is an acidic compound
  • the amycolamicin or the salts thereof can generally be produced by a known method using, for example, pharmaceutically acceptable various metals (e.g., alkali metals) or organic bases (e.g., quaternary ammonium salts).
  • the above microorganism belongs to the genus Amycolatopsis and is capable of producing the amycolamicin or the salt thereof.
  • the microorganism is not particularly limited and may be appropriately selected depending on the intended purpose, so long as it belongs to the genus Amycolatopsis and is capable of producing the amycolamicin or the salt thereof, and thus can be used as the amycolamicin-producing microorganisms in the above-described production method for the amycolamicin or the salt thereof.
  • MK575-fF5 strain preferably used are actinomycetes isolated from the soil of Sendai-shi, Miyagi and given accession number MK575-fF5 strain in May, 1996 by the microbial chemistry research center of Microbial Chemistry Research Foundation.
  • the mycological characteristics of the MK575-fF5 strain are as follows.
  • Substrate hyphae are well branched in a zig-zag form and are divided. Aerial hyphae are grown in some cases or not grown in other cases. When aerial hyphae are grown, the aerial hyphae are relatively long and linear or irregularly curved as well as divided into cylindrical spores. The surface is smooth and the size is about 0.4 ⁇ m to about 0.6 ⁇ m ⁇ about 0.8 ⁇ m to about 2.2 ⁇ m. Also, the aerial hyphae may be tangled together to have a spherical shape. Whorls, mycelial strands, sporangia and motile spores are not observed.
  • a partial nucleotide sequence (1,455 nt) of the 16S rRNA gene was determined and searched for homology based on international nucleotide sequence database (GenBank/DDBJ/EMBL).
  • the nucleotide sequence of the MK575-fF5 strain was found to have high homology with those of the 16S rRNA genes of actinomycetes belonging to the genus Amycolatopsis ; i.e., Amycolatopsis kentuckyensis (99.1%), Amycolatopsis rifamycinica (99.03%), Amycolatopsis mediterranei (98.9%), and Amycolatopsis balhimycetica (98.82%). Note that the values in parentheses are homology between the nucleotide sequences.
  • substrate hyphae of the MK575-fF5 strain are in a zig-zag form and divided.
  • Aerial hyphae are linear or irregularly curved and divided into cylindrical spores. Whorls, mycelial strands, sporangia and motile spores are not observed.
  • the MK575-fF5 strain is grown in colorless to yellowish orange in various media. Aerial hyphae of white to pale orange are formed in some cases or not formed in other cases. Soluble dyes are not produced.
  • the optimal growth temperature is about 30°C. This strain is negative in terms of the production of melanine-like dye and the hydrolysis of starch, but is positive in terms of reduction reaction of nitrate.
  • the hydrolyzates of each microorganism contain meso-2,6-diaminopimelic acid, arabinose and galactose, the cell wall is of Type IV, and the reducing sugars of each microorganism are of Type A. Also, mycolic acid is not contained and phospholipid is of Type PII (phosphatidylethanolamine is contained but phosphatidyl choline and unknown glucosamine-containing phospholipids are not contained) as well as a main menaquinone is MK-9(H 4 ).
  • Type PII phosphatidylethanolamine is contained but phosphatidyl choline and unknown glucosamine-containing phospholipids are not contained
  • nucleotide sequence of the 16S rRNA gene was found to have high homology with those of actinomycetes belonging to the genus Amycola topsis.
  • the MK575-fF5 strain was thought to belong to the genus Amycolatopsis (International Journal of Systematic Bacteriology, Vol. 36, pp. 29-37, 1986 ). Then, the MK575-fF5 strain was designated Amycolatopsis sp. MK575-fF5 strain. Notably, the MK575-fF5 strain was requested for deposition to the National Institute of Advanced Industrial Science and Technology, International Patent Organism Depositary and was accepted as FERM P-21465 on December 12, 2007.
  • a method for producing the amycolose derivatives or the salts thereof is not particularly limited and may be appropriately selected depending on the intended purpose. It is preferably a method including decomposing the amycolamicin or the salt thereof.
  • the method for the decomposing is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a hydrolysis method and a solvolysis method.
  • the hydrolysis method is preferably used.
  • the solvolysis method is preferably used.
  • the hydrolysis method is not particularly limited and may be appropriately selected depending on the intended purpose. It is preferably a hydrolysis method in which hydrolysis is performed with an acidic aqueous solution.
  • the acidic aqueous solution is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include an acetic acid aqueous solution, a sulfuric acid aqueous solution, a nitric acid aqueous solution and a hydrogen chloride aqueous solution.
  • the above acidic aqueous solutions may be used alone or in combination.
  • the temperature at which the hydrolysis is performed is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0°C to 100°C, more preferably 20°C to 40°C.
  • the time for which the hydrolysis is performed is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0.5 hours to 24 hours, more preferably 1 hour to 3 hours.
  • the method for terminating the hydrolysis reaction is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the hydrolysis reaction is terminated with, for example, any of a saturated sodium bicarbonate aqueous solution and various buffers.
  • the reaction mixture obtained after the hydrolysis is preferably extracted with a solvent since the compound 1 or the salt thereof can be obtained at higher concentrations.
  • the solvent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include ethyl acetate, diethyl ether, chloroform and dichloromethane.
  • the method for purifying the compound 1 after the extraction is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a method utilizing differences in adsorption affinity to various adsorbents, gel filtration, chromatography utilizing countercurrent distribution, and combinations thereof.
  • the solvolysis method is not particularly limited and may be appropriately selected depending on the intended purpose. It is preferably a solvolysis method in which solvolysis is performed with an alcohol solution, more preferably a solvolysis method in which solvolysis is performed with an acidic alcohol solution.
  • the alcohol solution is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include methanol, ethanol, n-propyl alcohol, i-propyl alcohol and n-butanol. The above alcohol solutions may be used alone or in combination.
  • the acid contained in the acidic alcohol solution is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include acetic acid, sulfuric acid, nitric acid and hydrogen chloride. These acids may be used alone or in combination.
  • the temperature at which the solvolysis is performed is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0°C to 100°C, more preferably 20°C to 40°C.
  • the time for which the solvolysis is performed is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0.5 hours to 24 hours, more preferably 1 hour to 3 hours.
  • the method for terminating the solvolysis reaction is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the hydrolysis reaction is terminated with, for example, any of a saturated sodium bicarbonate aqueous solution and various buffers.
  • the reaction mixture obtained after the solvolysis is preferably extracted with a solvent since at least one of the compounds 2 and 3 or the salts thereof can be obtained at higher concentrations.
  • the solvent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include ethyl acetate, diethyl ether, chloroform and dichloromethane.
  • the method for purifying at least one of the compounds 2 and 3 or the salt thereof after the extraction is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a method utilizing differences in adsorption affinity to various adsorbents, gel filtration, chromatography utilizing countercurrent distribution, and combinations thereof.
  • a pharmaceutical composition of the present invention contains the above-described amycolose derivative(s) (at least one of the compounds 1, 2 and 3) or the salts thereof; and, if necessary, further contains other ingredients.
  • the amount of the amycolose derivative(s) (at least one of the compounds 1, 2 and 3) or the salts thereof contained in the pharmaceutical composition is not particularly limited and may be appropriately selected depending on the intended purpose. Also, the pharmaceutical composition may be the amycolose derivative(s) or the salt thereof themselves.
  • the other ingredients are not particularly limited and may be appropriately selected from pharmacologically acceptable carriers depending on the intended purpose. Specific examples thereof include ethanol, water and starch.
  • the amount of the other ingredients contained in the pharmaceutical composition is not particularly limited and may be appropriately selected depending on the intended purpose, so long as the effects of the amycolose derivative(s) (at least one of the compounds 1, 2 and 3) or the salt thereof are not impeded.
  • the dosage form of the pharmaceutical composition is not particularly limited and may be appropriately selected depending on the intended purpose.
  • Examples of the dosage form include an oral solid preparation, an oral liquid preparation, an injection and an inhalation powder.
  • the oral solid preparation is not particularly limited and may be appropriately selected depending on the intended purpose.
  • examples of the oral solid preparation include a tablet, a coated tablet, granules, powder and a capsule.
  • the method for producing the oral solid preparation is not particularly limited and may be a routine method.
  • the oral solid preparation can be produced by adding an excipient and, if necessary, the above other ingredients and various additives to the amycolose derivative(s) (at least one of the compounds 1, 2 and 3) or the salt thereof.
  • the excipient is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose and silicic acid.
  • the additives are not particularly limited and may be appropriately selected depending on the intended purpose. Examples of the additives include a binding agent, a disintegrating agent, a lubricating .agent, a coloring agent and a sweetening/flavoring agent.
  • the binding agent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the binding agent include water, ethanol, propanol, simple syrup, glucose liquid, starch liquid, gelatine liquid, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylstarch, methylcellulose, ethylcellulose, shellac, calcium phosphate and polyvinylpyrrolidone.
  • the disintegrating agent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • examples of the disintegrating agent include dry starch, sodium alginate, powdered agar, sodium hydrogencarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate and lactose.
  • the lubricating agent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • examples of the lubricating agent include purified talc, stearic acid salts, borax and polyethylene glycol.
  • the coloring agent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • Examples of the coloring agent include titanium oxide and iron oxide.
  • the sweetening/flavoring agent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • Examples of the sweetening/flavoring agent include sucrose, orange peel, citric acid and tartaric acid.
  • the oral liquid preparation is not particularly limited and may be appropriately selected depending on the intended purpose.
  • Examples of the oral liquid preparation include an internal liquid, syrup and elixir.
  • the method for producing the oral liquid preparation is not particularly limited and may be a routine method.
  • the oral liquid preparation can be produced by adding an excipient and, if necessary, the above other ingredients and various additives to the amycolose derivative(s) (at least one of the compounds 1, 2 and 3) or the salt thereof.
  • the additives are not particularly limited and may be appropriately selected depending on the intended purpose. Examples of the additives include a sweetening/flavoring agent, a buffer and a stabilizing agent.
  • the sweetening/flavoring agent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • Examples of the sweetening/flavoring agent include sucrose, orange peel, citric acid and tartaric acid.
  • the buffer is not particularly limited and may be appropriately selected depending on the intended purpose.
  • Examples of the buffer include sodium citrate.
  • the stabilizing agent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • examples of the stabilizing agent include tragacanth, gum arabic and gelatin.
  • the injection is not particularly limited and may be appropriately selected depending on the intended purpose.
  • Examples of the injection include a solution, a suspension and a solid preparation reconstituted upon use.
  • the method for producing the injection is not particularly limited and may be a routine method.
  • the injection can be produced by optionally adding the above other ingredients, a pH adjuster, a buffer, a stabilizing agent, a tonicity agent, and a local anesthetic to the amycolose derivative(s) (at least one of the compounds 1, 2 and 3) or the salt thereof.
  • the pH adjuster or buffer is not particularly limited and may be appropriately selected depending on the intended purpose.
  • Examples of the pH adjuster or buffer include sodium citrate, sodium acetate and sodium phosphate.
  • the stabilizing agent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the stabilizing agent examples include sodium pyrosulfite, EDTA, thioglycolic acid and thiolactic acid.
  • the tonicity agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples of the tonicity agent include sodium chloride and glucose.
  • the local anesthetic is not particularly limited and may be appropriately selected depending on the intended purpose. Examples of the local anesthetic include procaine hydrochloride and lidocaine hydrochloride.
  • the administration method, the administration dose, the timing of administration and the subject to be administered are not particularly limited and may be appropriately selected depending on the intended purpose.
  • the administration method is not particularly limited and may be appropriately selected depending on the intended purpose.
  • Examples of the administration method include oral administration, injection and inhalation.
  • the administration dose is not particularly limited and may be appropriately selected considering various factors of a subject to be administered, such as the age, body weight, constitution, symptom and the presence or absence of administration of a drug containing other active ingredients.
  • the animal species serving as the subject to be administered is not particularly limited and may be appropriately selected depending on the intended purpose.
  • Examples of the animal species include human, monkey, pig, bovine, sheep, goat, dog, cat, mouse, rat and bird.
  • the pharmaceutical composition is suitably administered to human.
  • the pharmaceutical composition may be used alone or in combination with a drug containing other active ingredients. Also, the pharmaceutical composition may be formulated into a drug containing other active ingredients before use.
  • the pharmaceutical composition contains as an active ingredient(s) the amycolose derivative(s) (at least one of the compounds 1, 2 and 3) or the salt thereof, and thus has an excellent cell growth suppressive activity as shown in the below-described Test Example 1. Therefore, the pharmaceutical composition can suitably be used as a cell growth suppressive agent and is useful for the prevention or treatment of cancer.
  • the thus-obtained culture was centrifuged so as to be separated into 80 L of the culture filtrate and 2.5 kg of the microorganisms. Subsequently, 12 L of methanol was added to the microorganisms, and the resultant mixture was thoroughly stirred. Then, the compound having a structure expressed by the following Structural Formula (4) (hereinafter may be referred to as "amycolamicin”) was extracted from the microorganisms with methanol, followed by removal of methanol under reduce pressure, to thereby obtain 2 L of a microorganism extract containing amycolamicin.
  • amycolamicin Structural Formula (4)
  • the hexane-insoluble fraction (3.3 g) containing amycolamicin was dissolved in methanol, and the resultant solution was chromatographically separated with a Sephadex LH-20 (inner diameter: 28 mm ⁇ length: 450 mm, product of Pharmacia Biotech Inc.) column. The solution was fractionated every 8 g (one fraction) and, as a result, the active fractions were eluted as fractions 12 to 15. The fractions were collected and concentrated and dried under reduced pressure, to thereby obtain 1,584 mg of a crude product containing amycolamicin.
  • the chromatography was fractionated every 18 g (one fraction) and, as a result, amycolamicin was eluted as fractions 76 to 103. The fractions were collected and concentrated and dried under reduced pressure, to thereby obtain 827 mg of pure amycolamicin.
  • amycolamicin for physico-chemical properties, it was found to have the physico-chemical properties as shown below. From the physico-chemical properties, it was confirmed that the amycolamicin was the compound having a structure expressed by the following Structural Formula (4). Also, this amycolamicin was found to have tautomerism.
  • the residue was purified through thin-layer silica gel chromatography (developing solvent: ethyl acetate : methanol (95 : 5, by volume)) to thereby obtain ⁇ -methylglycoside compound (compound 2) and ⁇ -methylglycoside compound (compound 3).
  • the yield amount of the compound 2 was found to be 4.8 mg where the mole yield was 64%.
  • the yield amount of the compound 3 was found to be 2.5 mg where the mole yield was 33%.
  • Human prostate stromal cells PrSC (product of Bio Whittaker) were added to DMEM (product of NISSUI PHARMACEUTICAL CO., LTD.) containing 10% by mass FBS (fetal bovine serum) (product of ICN Biomedicals) to prepare a cell suspension having a concentration of 5 ⁇ 10 4 cells/mL.
  • the cell suspension was placed in a 96-well plate in an amount of 0.1 mL per well.
  • amycolose derivatives (compounds 1, 2 and 3) was added to the wells at a final concentration of 0.024 ⁇ g/mL, 0.098 ⁇ g/mL, 0.391 ⁇ g/mL, 1.563 ⁇ g/mL, 6.25 ⁇ g/mL, 25 ⁇ g/mL or 100 ⁇ g/mL, followed by culturing in an incubator for 3 days at 37°C and 5%CO 2 .
  • MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) (product of Sigma Co.), which had been adjusted with a phosphate buffer to have a concentration of 5 mg/mL, was added to each well in an amount of 10 ⁇ L, followed by culturing in an incubator for 4 hours at 37°C and 5%CO 2 . Subsequently, 100 ⁇ L of 20% by mass SDS (sodium dodecylsulphate) prepared with 10 mM hydrochloric acid was added to each well, and the plate was left to stand still overnight at 37°C to dissolve formazan formed from MTT.
  • SDS sodium dodecylsulphate
  • the plate was measured for absorbance at 570 nm with an absorptiometer (hereinafter may be referred to as "amycolose derivative-added sample's absorbance").
  • absorptiometer hereinafter may be referred to as "amycolose derivative-added sample's absorbance”
  • control absorbance the absorbance measured when no amycolose derivative was added
  • the cell growth rate in each of the amycolose derivatives (compounds 1, 2 and 3) at the above concentrations was calculated using the following equation (1). The results are shown in Fig. 5 .
  • Cell growth rate % amycolose derivative - added sample ⁇ s absorbance / control absorbance ⁇ 100
  • the amycolose derivatives (compounds 1, 2 and 3) were found to exhibit cell growth suppressive activity. Among them, the compound 1 was found to exhibit a remarkable cell growth suppressive activity.
  • amycolose derivatives or salts thereof according to the present invention have an excellent cell growth suppressive activity and thus can suitably be used as an active ingredient of a pharmaceutical composition that suppresses the growth of cancer cells and other cells.

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EP10811761.5A 2009-08-25 2010-08-19 Amycolose derivative, and production process and use of same Not-in-force EP2471788B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009194376A JP5502397B2 (ja) 2009-08-25 2009-08-25 新規化合物アミコロース誘導体、並びにその製造方法及びその用途
PCT/JP2010/064033 WO2011024711A1 (ja) 2009-08-25 2010-08-19 新規化合物アミコロース誘導体、並びにその製造方法及びその用途

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EP2471788B1 true EP2471788B1 (en) 2013-11-27

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US9126983B2 (en) 2009-12-23 2015-09-08 Merck Sharp & Dohme Corp. Extracts from kibdelos porangium as antibacterial agents

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JP2024521824A (ja) * 2021-05-27 2024-06-04 ヴァンダービルト ユニヴァーシティ マクロライド化合物

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WO2005100342A1 (en) * 2004-03-26 2005-10-27 Vertex Pharmaceuticals, Incorporated Pyridine inhibitors of erk2 and uses thereof
JP5283927B2 (ja) * 2008-02-28 2013-09-04 公益財団法人微生物化学研究会 新規化合物アミコラマイシン、その製造方法及びその用途

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US9126983B2 (en) 2009-12-23 2015-09-08 Merck Sharp & Dohme Corp. Extracts from kibdelos porangium as antibacterial agents

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CN102741243B (zh) 2014-11-05
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US8952140B2 (en) 2015-02-10
EP2471788A4 (en) 2013-02-20
US20120184728A1 (en) 2012-07-19
JP2011046622A (ja) 2011-03-10
CN102741243A (zh) 2012-10-17
WO2011024711A1 (ja) 2011-03-03

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